The present invention relates to an improved process for preparing methyl N-butyryl-4-amino-3-methylbenzoate and the novel chemical compound N-(4-bromo-2-methylphenyl)butanamide.
4xe2x80x2-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol)-2-yl]methyl]biphenyl-2-carboxylic acid is a valuable angiotensin antagonist, in particular a valuable angio-tensin II antagonist (see EP-A 502 314). In the following, these carboxylic acids are also known for short as antagonists.
In J. Med. Chem. 1993, 4040 a synthesis of the antagonist is described which starts from methyl 4-amino-3-methylbenzoate (I) and reacts it with butyryl chloride to give methyl N-butyryl-4-amino-3-methylbenzoate (II) (see the following reaction scheme (1)). 
Compound (II) is then converted in further steps to the antagonist.
The required starting compound of the formula (I) is only accessible in a disadvantageous manner. For instance, 4-nitro-m-xylene (III) can be used as the starting material and converted by oxidation to 4-nitro-2-methylbenzoic acid (IV) (see Liebigs Ann. Chem. 144, 163 (1867)), which is then esterified to methyl 4-nitro-2-methylbenzoate (V) (see Chem. Ber. 102, 2502 (1969)) and reduced to methyl 4-amino-3-methylbenzoate (I) (see Chem. Ber. loc. cit.). This process for preparing compound (II) is illustrated by the following reaction scheme (2). 
As can be seen, the known process for preparing compound (II) consists of four individual steps, and the first step (III)xe2x86x92(IV) is particularly disadvantageous because it requires long reaction times and leads only unselectively and therefore in low yields to (IV). According to J.O.C. 32, 134 (1967), a reaction time of 20 hours is required and the yields are from 22.5 to 27%.
There is accordingly still a need for a process for preparing compound (II) which requires fewer steps and provides compound (II) in an advantageous manner.
A process has now been found for preparing methyl N-butyryl-4-amino-3-methylbenzoate (II), which is characterized in that o-toluidine (VI) is reacted with butyryl chloride to give N-(2-methylphenyl)butanamide (VII), the latter is brominated to give N-(4-bromo-2-methylphenyl)butanamide (VIII) and this is converted by reaction with carbon monoxide and methanol in the presence of a palladium catalyst to give methyl N-butyryl-4-amino-3-methylbenzoate (II). The following reaction scheme (3) illustrates the process according to the invention. 
The stages (VII)xe2x86x92(VIII) and (VIII)xe2x86x92(II) are particularly surprisingly advantageous because they deliver (VIII) and (II) each in yields of over 95%.
The first stage of the process according to the invention, the reaction of compound (VI) with butyryl chloride to give compound (VII) may be carried out, for example, by initially charging compound (VI) in an inert solvent, for example an aromatic solvent such as chlorobenzene, toluene or xylene, and then metering in butyryl chloride at temperatures of, for example, 50 to 100xc2x0 C. In addition to the desired compound (VII), this also results in o-toluidine hydrochloride, which can, if desired, be completely converted to the amide by further heating. The progress of the reaction can be followed via the formation of hydrogen chloride. To destroy any remaining butyryl chloride residues, methanol can be added. After cooling the reaction solution, the amide (VII) precipitates and can be isolated, for example by filtration, in a purity of generally over 98% and in yields of generally from 92 to 95%.
The second stage of the process according to the invention, the bromination of compound (VII) to compound (VIII) may be carried out, for example, by initially charging the compound (VII) in acetic acid, adding from 1 to 1.3 molar quantity of elemental bromine together with further acetic acid at from 10 to 80xc2x0 C., continuing to stir the mixture at from 10 to 80xc2x0 C. for from 20 minutes to 3 hours, then adding a water quantity of from 0.5 to 5 times the volume, removing the precipitate formed, washing it with water and drying it under reduced pressure. Compound (VIII), i.e. N-(4-bromo-2-methylphenyl)butanamide can be obtained in this manner in yields of generally over 95% and in purities of generally over 99%.
The third step of the process according to the invention, the conversion of compound (VIII) by reaction with carbon monoxide and methanol in the presence of a palladium catalyst to compound (II) may be carried out, for example, by initially charging the compound of the formula (VIII) and a palladium catalyst into a pressure vessel, then adding a mixture of methanol, optionally one or more solvents other than methanol and a base, then pressurizing at from 90 to 160xc2x0 C. to 2-30 bar of carbon monoxide and maintaining this pressure until no more carbon monoxide is taken up.
In the third step of the process according to the invention, methanol may serve as a reaction partner and solvent. Optionally, one or more organic solvents other than methanol may additionally be used. Preferred additional organic solvents include hydrocarbons such as hexane, cyclohexane, heptane, benzene, toluene, the isomeric xylenes and mixtures thereof, chlorinated hydrocarbons such as chlorobenzene, dichlorobenzene, methylene chloride and hexachloroethane, nitriles such as acetonitrile, amides such as dimethylformamide and ethers such as dioxane and tetrahydrofuran. The use of such solvents is advantageous where it increases the solubility of carbon monoxide in the solution. This reaction stage can then be carried out at relatively low pressures, which on the industrial scale in particular is associated with lower apparatus and safety engineering demands.
The palladium catalysts used may, for example, be those of the Pd(P Ph3)2X2 type where Ph=optionally substituted phenyl and X=halogen, which may also be prepared in situ from PdX2 and PPh3. The triphenylphosphine component may also be added in excess. Based on compound (VIII), for example, from 0.1 to 1 mol % of palladium catalyst may be used.
Examples of useful bases include carbonates, hydrogen carbonates and acetates of alkali metals. However, preference is given to primary, secondary and tertiary amines, in particular tri-C1-C10-alkylamines. Based on 1 mol of compound (VIII), for example, from 0.9 to 5 mol, preferably from 1.05 to 2 mol, of base can be used.
The process according to the invention provides compound (II) in an only 3-step process in good yields and in good purities. The yield in the process according to the invention over all three steps is generally from 90 to 95%. This is a substantial improvement in accessibility to compound (II) and to the antagonists preparable from compound (II).
One embodiment of the process according to the invention is a synthesis of (VIII) without intermediate isolation of compound (VII). This is technically advantageous, since the intermediate isolation of a compound always requires additional apparatus, which slow the process and generally reduce the yield by isolation losses and residues, for example in mother liquors.
In this embodiment, the initial procedure is as described for preparing compound (VII). The crude solution of (VII) obtained by amidation is freed of the inert solvent after butyrylation by distillation. In order to remove remaining residues of the inert solvent, water may be added to the melt of compound (VII) and distilled off again. The crude (VII) obtained may then be admixed with a solvent suitable for bromination. This is preferably acetic acid, formic acid, propionic acid or mixtures thereof with water in any ratio and also dilute mineral acids such as sulfuric acid or just water. Bromination in an inert solvent with addition of Lewis acids, for example aluminum chloride, aluminum bromide, iron bromide, or with addition of elemental iron, is likewise possible. Particular preference is given to acetic acid and also to mixtures of acetic acid and water. Bromine is added directly to this reaction mixture at temperatures of from 10 to 130xc2x0 C., preferably from 30 to 60xc2x0 C. Based on 1 mol of compound (VII), from 0.9 to 1.1 mol of bromine to from 1 to 1.05 mol can be added.
Owing to the resulting hydrobromic acid, only half of the valuable bromine used can be converted. Accordingly, this embodiment contemplates using only from 0.45 to 0.95 mol of bromine for 1 mol of compound (VII) and carrying out the further bromination via reoxidation of hydrobromic acid using an oxidant, preferably hydrogen peroxide, in a quantity supplementary to 1 mol.
The bromination can also be carried out using hydrobromic acid, and adding an oxidant after its addition. For example, from 0.9 to 1.1 mol of hydrobromic acid per mole of compound (VII) and an equivalent quantity of oxidant, preferably hydrogen peroxide, can be used. If appropriate, hydrobromic acid can also be used as a solution in water. Instead of hydrobromic acid, bromides can also be used, preferably potassium bromide. Bromides can also be used as such or, for example, in aqueous solution.
A technical problem in all of the above-described syntheses is that the product (VIII) of the bromination, owing to its solubility properties, precipitates after the reaction has proceeded to from about 30 to 70% spontaneously and as a fine solid. The resulting suspension can only be stirred with difficulty. An industrial reaction can accordingly only be carried out at huge cost and inconvenience.
This problem is surprisingly solved by carrying out the bromination in the form of simultaneous metering in (with a tolerance of up to 20%, preferably from 10 to 20%, in the respective volume flow rates) of the bromine or the bromine and the oxidant on the one hand and the crude (VII), optionally a mixture of (VII) and the solvent suitable for bromination, on the other hand. The reactants may be metered into a reservoir in which a portion of the solvent suitable for bromination is present. This embodiment is likewise part of the subject matter of the process according to the invention. Preferred initial charges include mixtures of acetic acid and water in a ratio of from 0.2:0.8 to 0.8:0.2. Particularly preferred 0.25:0.75 to 0.5:0.5. The crystallization behavior was also improved by adding and also compound (VIII) (slightly soluble) to the reservoir before bromination to give a suspension.
The compound of the formula (VIII) is novel. The present invention also accordingly relates to the compound of the formula (VIII), i.e. N-(4-bromo-2-methylphenyl)butanamide. This compound can be prepared as described above. It provides the key substance in the process according to the invention for preparing the compound of the formula (II). Its discovery facilitated improved access to the compound of the formula (II) and the antagonists preparable from it.